PROJECT SUMMARY/ABSTRACT In order to uncover novel genetic variants that influence tau toxicity, and also recapitulate the genetic diversity characteristic of the human population, Project 2 aims to take advantage of the observation that severity of tauopathy in transgenic mouse models is significantly impacted by altering genetic background. While most transgenic lines have been created on a standard genetic background, a single inbred strain does not incorporate one of the major sources of phenotypic variation in human populations: genetic diversity. The lack of genetic diversity also limits the translational utility of standard mouse models because it grossly underestimates the variation of responses that will be seen in the human population. Therefore a genetically- diverse mouse model of tauopathy will be created in the current study, using AAV to drive mutant tau expression in a panel of Collaborative Cross (CC) recombinant inbred mice, as well as Diversity Outbred (DO) mice produced from random repeated outcrossing of CC strains. Collectively, the CC and DO mouse populations offer high mapping resolution and broad allelic diversity, carrying 45 million SNPs and structural variants and thus providing a unique opportunity to discover new genes that regulate tau toxicity in vivo. Although there are currently no genetically diverse models of tauopathy that are representative of the diversity present within the human population, the development of such a model would enable researchers to test the efficacy and toxicity of new therapeutic strategies, improving translational relevance by incorporating the genetic variation missing from traditional models. Here, based on the compelling evidence presented in Project 3 demonstrating that antibody-induced elevation of plasma tau fluctuates with disease progression, we will evaluate the extent to which genetic background and disease severity influence plasma tau levels in our AAV-injected, CC and DO mice. These findings will not only provide key insight into the potential significance of changes in plasma tau concentrations to progression of tauopathy, but also offer an indication of the magnitude of variability that could be anticipated in the human population. Collectively, the studies proposed will not only increase our understanding of underlying pathogenic mechanisms and pathways, but also drive the identification of new therapeutic targets for the treatment of tauopathy.